Use of adjuvant containing mycobacterial cell-wall skeleton, monophosphoryl lipid A, and squalane in malaria circumsporozoite protein vaccine

Rickman, LelandS.; Wistar, Richard; Hoffman, Stephen L.; Gordon, Daniel M.; Krzych, Urszula; Egan, James E.; Chulay, Jeffrey D.; Gross, Mitchell; Hollingdale, Michael R.

doi:10.1016/0140-6736(91)92659-p

Cited by 78 publications

(29 citation statements)

References 11 publications

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“…The results ofthis trial confirm the previous findings ofsafety and enhanced immunogenicity observed in animals. Encapsulation of R32NS181 in MPLA-containing liposomes, followed by adsorption to Al(OH)3, induced the production of R32-specific IgG concentrations that were 5-to 15-fold greater after three doses than those developed after four doses ofAl(OH)3 -adsorbed R32NS18, (1150 Mg per dose) and comparable to results obtained after three doses with the "Detox" adjuvant in other studies (14).…”

Section: Methodssupporting

confidence: 70%

“…These results suggest that a potent immune response could probably have been achieved at a dose of <6.3 jg of antigen, which again contrasts with a previous candidate vaccine that used 1150 pg per dose of the same antigen adsorbed to Al(OH)3 (14). The effectiveness of low doses of liposomal antigen could have potentially useful implications in those instances in which antigen is very expensive or in short supply.…”

Section: Methodscontrasting

confidence: 49%

“…The success of this approach in animals resulted in initiation of the present clinical trial. The recombinant antigen used in the current study (R32NS181) has also been recently evaluated in humans with other adjuvant systems that were more effective than Al(OH)3 but less potent than the liposome formulation used in the present study (14). …”

mentioning

confidence: 99%

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Liposomal malaria vaccine in humans: a safe and potent adjuvant strategy.

Fries

Gordon

Richards

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

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209

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This study describes the safety and immunogenicity of a liposome-based vaccine injected into human subjects. Thirty healthy adult male volunteers were immunized with a liposome-encapsulated recombinant protein (R32NS181) containing epitopes from the repeat region of the circumsporozoite protein of Plasmodium falciparum. This antigen had previously been found to be poorly immunogenic in humans when it was adsorbed with Al(OH)3. In the present study, R32NS181 was encapsulated in liposomes containing monophosphoryl lipid A that were subsequently adsorbed to Al(OH)3. Increasing doses of liposomes containing antigen and monophosphoryl lipid A were used, but the liposomes were always adsorbed to the same dose of Al(OH)3. R32-specific serum IgG antibody responses to liposome-encapsulated R32NS181 were much higher than levels attained previously in humans with R32NS181 adsorbed to Al(OH)3. Geometric mean specific IgG levels after three doses ranged from 14 to 33 pg/ml. Sera from volunteers receiving the two highest doses inhibited P. falkiparum sporozoite invasion of cultured hepatoma cells by an average of 92%, a result that was again superior to previously reported vaccines. Moderate but acceptable transient local reactogenicity was noted at high doses of the vaccine formulation, but little or no systemic toxicity was seen despite liposomal monophosphoryl lipid A doses up to 2200 pug.We conclude that encapsulation of poorly immunogenic circumsporozoite protein repeat peptides in monophosphoryl lipid A-containing liposomes is a successful adjuvant strategy in humans for inducing high levels of specific antibody production.Practical development of modern vaccines has been greatly advanced by the availability of synthetic antigens, but progress has been hindered in some cases by poor immunogenicity ofthe antigens. Liposomes have been successfully used as drug carriers (1) Although some protective immunity against experimental P. falciparum challenge was achieved after immunization of humans with an Al(OH)3-adsorbed recombinant protein (7) or a peptide-tetanus toxoid conjugate (7) containing repeat epitopes, the immune response was poor (7-9).In an effort to improve the humoral immune response, we designed and tested in animals a variety of Al(OH)3-adsorbed candidate liposomal vaccines containing lipid A or monophosphoryl lipid A (MPLA) and repeat-based malaria antigens (10-13). The success of this approach in animals resulted in initiation of the present clinical trial. The recombinant antigen used in the current study (R32NS181) has also been recently evaluated in humans with other adjuvant systems that were more effective than Al(OH)3 but less potent than the liposome formulation used in the present study (14). MATERIALS AND METHODSAntigen. The antigen, designated R32NS181 (also called R32NS1), was expressed in Escherichia coli and purified by SmithKline Beecham Pharmaceuticals. It consists of a fusion protein with the amino acid sequence MDP[(NANP)15-(NVDP)]2NS181 (13). NS181, which refers to a sequence of 81...

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Section: Methodssupporting

confidence: 70%

Section: Methodscontrasting

confidence: 49%

See 1 more Smart Citation

Liposomal malaria vaccine in humans: a safe and potent adjuvant strategy.

Fries

Gordon

Richards

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

209

View full text Add to dashboard Cite

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“…The third was Detox, an investigational adjuvant consisting of cell wall skeleton from Mycobacterium phlei and MPL emulsified in squalane, which has been designed as a replacement of complete Freund adjuvant. Detox has been used in both animals and humans to enhance immunological responses to vaccine antigens (28,47). The fourth was QS-21, a triterpene glycoside from Quillaja saponaria Molina cortex, which stimulates both cellular (Th1) and humoral immune responses and has been used in human vaccination trials with a variety of antigens (44,45,51).…”

Section: Resultsmentioning

confidence: 99%

Subunit Vaccination of Mice against New World Cutaneous Leishmaniasis: Comparison of Three Proteins Expressed in Amastigotes and Six Adjuvants

et al. 2000

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A mixture of well-defined recombinant antigens together with an adjuvant that preferentially stimulates specific gamma interferon (IFN-␥)-secreting helper type 1 CD4 ؉ T cells (Th1 cells) presents a rational option for a vaccine against leishmaniasis. The potential of this approach was investigated in murine infections with Leishmania mexicana, which are characterized by the absence of a parasite-specific Th1 response and uncontrolled parasite proliferation. A mixture of three antigens (glycoprotein 63, cysteine proteinases, and a membrane-bound acid phosphatase), which are all expressed in amastigotes, the mammalian stage of the parasite, were used for the immunization of C57BL/6 mice in combination with six adjuvants (interleukin 12 [IL-12], Detox, 4-monophosphoryl lipid A, QS-21, Mycobacterium bovis BCG, and Corynebacterium parvum). All six vaccine formulations containing the mixture of recombinant antigens were protective against challenge infections with promastigotes, the insect stage of the parasite, in that mice controlled and healed infections but developed transient and, in certain cases, accentuated disease. The most effective adjuvants were IL-12 followed by Detox. Further studies using these two adjuvants showed that a similar protective effect was observed with a mixture of the corresponding native proteins, and mice which had controlled the infection showed a preponderance of IFN-␥-secreting CD4 ؉ T cells in the lymph nodes draining the lesion. Using the recombinant proteins individually, it is shown that the relatively abundant cysteine proteinases and glycoprotein 63, but not the acid phosphatase, are able to elicit a protective response. The results are discussed in comparison to previous studies with subunit vaccines and with respect to cell biological aspects of antigen presentation in Leishmania-infected macrophages.The solid immunity observed following recovery from cutaneous leishmaniasis in humans has stimulated numerous attempts for the development of a prophylactic vaccination against this widespread (sub)tropical disease (12,16,19,35,36). Leishmania major, the etiological agent of Old World cutaneous leishmaniasis, has been the most popular species both in studies of murine infections and in human trials. In the Middle East, the deliberate infection with L. major was a common and effective practice for immunization against subsequent infections, but a fraction of the vaccinated persons produced lesions that required medical treatment. A vaccine based on killed promastigotes, the insect stage of the parasite, and Mycobacterium bovis BCG was recently shown to be ineffective in a controlled trial with several thousand volunteers in Iran (37). Mice have been used in a range of vaccination protocols against infection by L. major. Representative examples include: attenuated but live parasites (23,29,34,48,59); subunit vaccines delivered by live carriers such as BCG expressing the surface proteinase GP63 of L. major (11); vaccinia virus expressing the glycoprotein GP46/M-2 (20, 30); GP63 expr...

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“…It is unclear in this study whether mixing the MPL with trehalose dimycolate, a strong immunomodulator, would alter the im-munobiological characteristics of MPL. Recent and previous human clinical trials of malaria circumsporozoite protein and blood-stage antigens, including MSP1, have used combination adjuvant formulations containing MPL derivatives (9,32,37,39). Induction of biologically active antibodies was demonstrated in these studies.…”

Section: Discussionmentioning

confidence: 95%